The overall objective of this project is to determine the factors which regulate the uptake and metabolism of fatty acids by the liver and which thereby influence the availability of fatty acids for lipoprotein formation. A segment of this work will be devoted to providing better definition of the fatty acid supply in this tissue, with particular reference to de novo fatty acid synthesis. Regulation of the partition of fatty acids between the pathways of esterification and oxidation will be studied in intact liver cells and also in the following subcellular systems: (a) mitochondria for studies on fatty acid oxidation and ketogenesis and (b) microsomes for studies on esterification. Certain of these systems will also include the cytosolic fraction. Submitochondrial systems will also be employed, mainly for studies on the localization of the enzymes of ketogenesis. Experiments will also be conducted on the mechanisms by which other substrates alter the utilization of long-chain fatty acids in this tissue. Hepatic tissue derived from rats in various physiological states will be employed. Various aspects of the terminal processing of acetyl units, derived from fatty acid oxidation, in the citric acid cycle and ketogenesis will be investigated at the cellular and subcellular level.